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PRODUCT MONOGRAPH
Pr
INHIBACE®
cilazapril tablets
2.5 mg and 5.0 mg
angiotensin converting enzyme inhibitor
Hoffmann-La Roche Limited
7070 Mississauga Road
Mississauga, Ontario
L5N 5M8
www.rochecanada.com
Date of Preparation:
March 22, 1993
Date of Revision:
March 12, 2015
 Copyright 1993 - 2015 Hoffmann-La Roche Ltd
Submission Control No: 180630
INHIBACE is a registered trade-mark of Hoffmann-La Roche Limited, used under license.
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3 INDICATIONS AND CLINICAL USE ..............................................................................3 CONTRAINDICATIONS ...................................................................................................4 WARNINGS AND PRECAUTIONS ..................................................................................5 ADVERSE REACTIONS..................................................................................................12 DRUG INTERACTIONS ..................................................................................................19 DOSAGE AND ADMINISTRATION ..............................................................................25 OVERDOSAGE ................................................................................................................27 ACTION AND CLINICAL PHARMACOLOGY ............................................................28 STORAGE AND STABILITY ..........................................................................................31 SPECIAL HANDLING INSTRUCTIONS .......................................................................31 DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................32 PART II: SCIENTIFIC INFORMATION ...............................................................................33 PHARMACEUTICAL INFORMATION..........................................................................33 DETAILED PHARMACOLOGY .....................................................................................34 MICROBIOLOGY ............................................................................................................36 TOXICOLOGY .................................................................................................................37 REFERENCES ..................................................................................................................46 PART III: CONSUMER INFORMATION..............................................................................48 Page 2 of 52
Pr
INHIBACE®
cilazapril tablets
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage Form /
Strength
Non-medicinal Ingredients
oral
tablet 2.5 mg, 5 mg
Lactose monohydrate, cornstarch,
hydroxypropyl methylcellulose, talc, sodium
stearyl fumarate and titanium dioxide. Iron
oxide is present as the colouring agent in the
tablet.
INDICATIONS AND CLINICAL USE
INHIBACE (cilazapril) is indicated in the treatment of mild to moderate essential hypertension.
INHIBACE may be used alone or in combination with thiazide-type diuretics. INHIBACE is
also indicated in the treatment of congestive heart failure as an adjunctive therapy with digitalis
and/or diuretics.
In using INHIBACE consideration should be given to the risk of angioedema (see WARNINGS
AND PRECAUTIONS).
Hypertension
INHIBACE should normally be used in those patients in whom treatment with a diuretic or a
beta-blocker was found ineffective or has been associated with unacceptable adverse effects.
INHIBACE can also be tried as an initial agent in those patients in whom use of diuretics and/or
beta-blockers is contraindicated or in patients with medical conditions in which these drugs
frequently cause serious adverse effects.
The safety and efficacy of INHIBACE in renovascular hypertension has not been established and
therefore, its use in this condition is not recommended.
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The safety and efficacy of concomitant use of INHIBACE with antihypertensive agents other
than thiazide diuretics has not been established.
Congestive Heart Failure
INHIBACE is indicated in the treatment of congestive heart failure as adjunctive therapy in
patients who have not responded adequately to digitalis and/or diuretics. There is limited data on
New York Heart Association Class IV patients (see ACTIONS AND CLINICAL
PHARMACOLOGY). Treatment with INHIBACE should be initiated in patients with
congestive heart failure under close medical supervision.
Geriatrics:
Although clinical experience has not identified differences in response between the elderly and
younger patients, greater sensitivity of some older individuals cannot be ruled out. In elderly
patients with congestive heart failure on high diuretic dosage, the recommended starting dose of
INHIBACE 0.5 mg must be strictly followed (see WARNINGS AND PRECAUTIONS,
Geriatrics).
Pediatrics:
The safety and effectiveness of the use of INHIBACE in children have not been established.
Therefore, use in this age group is not recommended.
CONTRAINDICATIONS
INHIBACE (cilazapril) is contraindicated in:

Patients who are hypersensitive to cilazapril, any ingredient in the formulation or
component of the container. For a complete listing, see the Dosage Forms, Composition
and Packaging section of the product monograph.

Patients with hereditary/idiopathic angioedema or a history of angioedema related to
previous treatment with an angiotensin converting enzyme inhibitor (see WARNINGS
AND PRECAUTIONS, General).

Patients with anuria

Patients with ascites
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
Women who are pregnant, intend to become pregnant, or of childbearing potential who
are not using adequate contraception (see WARNINGS AND PRECAUTIONS: Serious
Warnings and Precautions and Special Populations, Pregnant Women and ADVERSE
REACTIONS).

Nursing Women (see WARNINGS AND PRECAUTIONS: Special Populations, Nursing
Women).

Combination with aliskiren-containing drugs in patients with:
 diabetes mellitus (type 1 or type 2)
 moderate to severe renal impairment (GFR < 60 ml/min/1.73 m2) (see
WARNINGS and PRECAUTIONS, Dual Blockade of the Renin-Angiotensin
System (RAS) and Renal, and DRUG INTERACTIONS, Dual Blockade of the
Renin-Angiotensin System (RAS) with ACE inhibitors, ARBs or aliskirencontaining drugs).

Patients with hereditary problems of galactose intolerance, glucose-galactose
malabsorption, or the Lapp lactase deficiency as INHIBACE® contains lactose (see
WARNINGS AND PRECAUTIONS, Sensitivity/Resistance)
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
The use of INHIBACE (cilazapril) is contraindicated during pregnancy (see
CONTRAINDICATIONS). When used in pregnancy, angiotensin converting enzyme (ACE)
inhibitors can cause injury or even death of the developing fetus. Pregnant women should be
informed of the potential hazards to the fetus and must not take INHIBACE during pregnancy.
Patients planning pregnancy should be changed to alternative antihypertensive treatments which
have an established safety profile for use in pregnancy. When pregnancy is detected, INHIBACE
should be discontinued as soon as possible and, if appropriate, alternative therapy should be
started (see WARNINGS AND PRECAUTIONS).
Cardiovascular
Angioedema
Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors
including INHIBACE. Angioedema has been associated with ACE inhibitors, with a reported
incidence of 0.1-0.5%. Angioedema due to ACE inhibitors can present as recurrent episodes of
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facial swelling, which resolve on withdrawal, or as acute oropharyngeal edema and potentially
life-threatening airway obstruction, which requires emergency treatment. Angioedema associated
with laryngeal edema and/or shock may be fatal. If angioedema occurs, INHIBACE (cilazapril)
should be promptly discontinued and appropriate therapy instituted without delay. A variant
form is angioedema of the intestine, which tends to occur within the first 24-48 hours of
treatment.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at an increased
risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).
Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors or
dipeptidyl peptidase IV (DPP-IV) inhibitors may lead to an increased risk for angioedema.
Caution should be used when using mTOR inhibitors or DPP-IV inhibitors concomitantly with
ACE inhibitors (see DRUG INTERACTIONS, Drug-Drug Interactions).
Aortic Stenosis/Hypertrophic Cardiomyopathy
As with other ACE inhibitors, INHIBACE should be used with caution in patients with
obstructive cardiac disorders (e.g. mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy),
since cardiac output cannot increase to compensate for systemic vasodilation, and there is a risk
of severe hypotension.
There is concern on theoretical grounds that patients with aortic stenosis might be at particular
risk of decreased coronary perfusion when treated with vasodilators because they do not develop
as much afterload reduction.
Hypotension
INHIBACE, like other ACE inhibitors, may cause severe hypotension, especially when starting
treatment, usually after the first dose or when the dose had been increased. First-dose
hypotension is most likely to occur in patients whose renin-angiotensin-aldosterone system is
activated, such as in renovascular hypertension or other causes of renal hypoperfusion, sodium or
volume depletion, previous treatment with other vasodilators and in patients with dietary salt
restriction, dialysis, diarrhea, or vomiting. These conditions can co-exist, particularly in severe
heart failure.
Patients with congestive heart failure, especially those vigorously treated with loop diuretics,
may experience excessive hypotension in response to ACE inhibitors. Because of the potential
fall in blood pressure in these patients, therapy should be started under very close medical
supervision. Such patients should be followed closely for the first two weeks of treatment and
whenever the dose of INHIBACE and/or diuretic is increased. Similar considerations may apply
to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood
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pressure could result in a myocardial infarction or cerebrovascular accident (see ADVERSE
REACTIONS).
Patients at risk for hypotension should start treatment with cilazapril under medical supervision,
with a low initial dose and careful titration. If possible, diuretic therapy should be discontinued
temporarily.
Similar caution should be taken for patients with angina pectoris or cerebrovascular disease, in
whom hypotension can cause myocardial or cerebral ischemia.
In patients with severe heart failure, whose renal function may depend on the activity of the
renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including INHIBACE,
may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or
death.
Hypotension should be treated by placing the patient supine and with volume expansion.
Cilazapril may be continued once the patient is volume replete, but should be given at a lower
dose or discontinued if hypotension persists.
Dual Blockade of the Renin-Angiotensin System (RAS)
There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors,
such as INHIBACE, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the
risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including
renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal
impairment (GFR < 60 ml/min/1.73m2). Therefore, the use of INHIBACE in combination with
aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).
Further, co-administration of ACE inhibitors, including INHIBACE, with other agents blocking
the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other
patients, since such treatment has been associated with an increased incidence of severe
hypotension, renal failure, and hyperkalemia.
Ear/Nose/Throat
Cough
A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose
of INHIBACE, has been reported.
Such possibility should be considered as part of the differential diagnosis of the cough.
Endocrine and Metabolism
Diabetes
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Administration of ACE inhibitors to patients with diabetes may potentiate the blood glucose
lowering effect of oral hypoglycemic agents or insulin, especially in patients with renal
impairment. In such patients, glucose levels should be carefully monitored during initiation of
treatment with an ACE inhibitor.
Ethnicity
ACE inhibitors are less effective as antihypertensives in black-skinned patients of African
descent. Black-skinned patients also have a higher risk of angioedema.
Hematologic
Neutropenia/Agranulocytosis
Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Cases of
leucopenia and neutropenia have rarely been reported in patients treated with ACE Inhibitors.
Periodic monitoring of white blood cell counts should be considered in patients with collagen
vascular disease and renal disease such as systemic lupus erythematosus and scleroderma, or in
patients receiving immunosuppressive therapy, especially when they also have impaired renal
function.
Hepatic
Patients With Impaired Liver Function
Hepatitis (hepatocellular and/or cholestatic), jaundice, elevations of liver enzymes and/or serum
bilirubin have occurred during therapy with cilazapril in patients with or without pre-existing
liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.
Cases of liver function disorders, such as increased values of liver function tests (transaminases,
bilirubin, alkaline phosphatase, gamma GT) and cholestatic hepatitis have been reported. Patients
receiving cilazapril who develop jaundice or marked elevations of hepatic enzymes should
discontinue cilazapril and receive appropriate medical follow-up.
There are no adequate studies in patients with cirrhosis and/or liver dysfunction. INHIBACE
should be used with particular caution in patients with pre-existing liver abnormalities. In such
patients baseline liver function tests should be obtained before administration of the drug and
close monitoring of response and metabolic effects should apply.
In patients with liver cirrhosis (but without ascites) who require therapy for hypertension,
cilazapril should be initiated at a lower dose and with great caution because significant
hypotension may occur. In patients with ascites, cilazapril administration is not recommended.
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Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism
of this syndrome is not understood.
Hyperkalemia
ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The
effect is usually not significant in patients with normal renal function. However, in patients with
impaired renal function and/or in patients taking potassium supplements (including salt
substitutes) or potassium-sparing diuretics, and especially aldosterone antagonists, hyperkalemia
can occur. Potassium-sparing diuretics should be used with caution in patients receiving ACE
inhibitors, and serum potassium and renal function should be monitored.
In clinical trials, elevated serum potassium (greater than 5.5 mEq/L) was observed in
approximately 0.7% of hypertensive patients and 0.8% of congestive heart failure patients
receiving cilazapril. In most cases these were isolated values which resolved despite continued
therapy, however in one case the patient discontinued treatment. Risk factors for the
development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the
concomitant use of agents to treat hypokalemia (see DRUG INTERACTIONS and ADVERSE
REACTIONS).
Immune
Anaphylactoid Reactions during Membrane Exposure
Hemodialysis: Anaphylactoid reactions have been reported in patients dialysed with high-flux
membranes (e.g., polyacrylonitrile [PAN], AN 69) and treated concomitantly with an ACE
inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal
cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are
not relieved by antihistamines. In these patients, consideration should be given to using a
different type of dialysis membrane or a different class of antihypertensive agent.
Anaphylactoid Reactions during Low Density Lipoproteins (LDL) Apheresis
Patients receiving ACE inhibitors during LDL apheresis with dextran sulfate have experienced
life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily
withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactoid Reactions during Desensitization
There have been reports of patients experiencing sustained life threatening anaphylactoid
reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees,
wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors
were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent
rechallenge.
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Cilazapril use must be stopped before the start of desensitization therapy and must not be
replaced by a beta-blocker.
Nitritoid Reactions – Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and symptomatic
hypotension) have been reported rarely in patients on therapy with injectable gold (sodium
aurothiomalate) and concomitant ACE inhibitor therapy including INHIBACE (see DRUG
INTERACTIONS).
Peri-Operative Considerations
Surgery/Anesthesia
In patients undergoing major surgery or during anesthesia with agents that produce hypotension,
cilazapril blocks angiotensin II formation, secondary to compensatory renin release. This may
result in arterial hypotension which can be corrected by volume expansion.
Renal
Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal
function have been seen in susceptible individuals. In patients whose renal function may depend
on the activity of the renin-angiotensin aldosterone system, rarely, acute renal failure have been
reported such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a
solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system
has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or
death. In susceptible patients, concomitant diuretic use may further increase risk and produce
increases in blood urea nitrogen and/or serum creatinine. Although these alterations are usually
reversible upon discontinuation of INHIBACE and/or diuretic therapy, cases of severe renal
dysfunction and, rarely, acute renal failure have been reported. In susceptible patients,
concomitant diuretic use may further increase risk.
When treated with cilazapril, patients with renal artery stenosis have an increased risk of renal
insufficiency, including acute renal failure. Therefore, caution should be exercised in these
patients.
Use of INHIBACE should include appropriate assessment of renal function.
Reduced dosages may be required for patients with renal impairment depending on their
creatinine clearance (see DOSAGE AND ADMINISTRATION, Dosage Adjustment in Patients
with Renal Impairment).
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The use of ACE inhibitors – including INHIBACE – or ARBs with aliskiren-containing drugs is
contraindicated in patients with moderate to severe renal impairment (GFR < 60 ml/min/1.73m2).
(See CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the ReninAngiotensin-System (RAS) with ARBs, ACE inhibitors, or aliskiren-containing drugs).
Sensitivity/Resistance
Lactose Intolerance
INHIBACE tablets contain lactose monohydrate. Therefore, patients with hereditary galactose
intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicine (see CONTRAINDICATIONS).
Special Populations
Pregnant Women:
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to
pregnant women. The use of cilazapril is contraindicated during pregnancy. Pregnant women
should be informed of the potential hazards to the fetus and must not take INHIBACE during
pregnancy (see CONTRAINDICATIONS). Patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for use in
pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped
immediately, and, if appropriate, alternative therapy should be started.
Fetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be
associated with prematurity, an increased risk of malformations of the cardiovascular (atrial
and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous
system (microcephaly, spina bifida) and of kidney malformations.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce
human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation)
and neonatal toxicity (hypotension, hyperkalemia, neonatal skull hypoplasia, intrauterine growth
restriction, anuria, renal tubular dysplasia, reversible or irreversible renal failure and death).
Oligohydramnios reported with the use of ACE inhibitors presumably resulted from decreased
fetal renal function, associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Should exposure to ACE inhibitors have occurred from the
second trimester of pregnancy, ultrasound examination of renal function and skull is
recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for
hypotension.
Infants with a history of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required
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as a means of reversing hypotension and/or substituting for impaired renal function; however,
limited experience with those procedures has not been associated with significant clinical
benefit.
Dialysis clearance was estimated to be 2.4 L/h for cilazapril and 2.2-2.8 L/h for cilazaprilat.
Animal Data: In fertility and general reproduction performance testing in rats, dosing with
50 mg/kg/day of cilazapril resulted in greater implantation losses, less viable fetuses, smaller
pups, and dilatation of the renal pelvis in the pups. No teratogenic effects and no adverse effects
on postnatal pup development were observed in rats and cynomolgus monkeys during
embryotoxicity testing. In the rats, however, at a dose of 400 mg/kg/day, renal cavitation was
observed in the pups. In peri- and post-natal toxicity testing in rats, dosing with 50 mg/kg/day
resulted in greater pup mortality, smaller pups, and delayed unfolding of the pinna. On
administration of 14C-cilazapril to pregnant mice, rats and monkeys, radioactivity was measured
in the fetuses.
Nursing Women:
Animal data show the presence of cilazaprilat in rat milk. However, no information is available
regarding the safety of cilazapril during breast-feeding in humans. INHIBACE must not be
administered to nursing mothers (see CONTRAINDICATIONS) and alternative treatments with
better established safety profiles during breast-feeding are preferable.
Ability to Drive and Use Machines:
Occasionally dizziness and fatigue may occur, especially when starting therapy (see ADVERSE
REACTIONS).
Pediatrics:
The safety and effectiveness of the use of INHIBACE in children have not been established.
Therefore, use in this age group is not recommended.
Geriatrics:
Although clinical experience has not identified differences in response between the elderly and
younger patients, greater sensitivity of some older individuals cannot be ruled out. In elderly
patients with congestive heart failure on high diuretic dosage, the recommended starting dose of
INHIBACE 0.5 mg must be strictly followed (see WARNINGS AND PRECAUTIONS,
Cardiovascular, Hypotension, and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Adverse Drug Reaction Overview
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Headache and dizziness were the most frequently reported events in patients taking INHIBACE
for hypertension. In chronic heart failure clinical trials, dizziness and coughing were the most
frequently reported events in patients taking INHIBACE.
The most frequent drug-attributable adverse events observed in patients taking ACE inhibitors
are cough, skin rash and renal dysfunction. Cough is more common in women and non-smokers.
Where the patient can tolerate the cough, it may be reasonable to continue treatment. In some
cases, reducing the dose may help.
Treatment-related adverse events severe enough to stop treatment occur in less than 5% of
patients receiving ACE inhibitors.
Hypotension and postural hypotension may occur when starting treatment or increasing dose,
especially in at-risk patients (see WARNINGS AND PRECAUTIONS).
Renal impairment and acute renal failure are more likely in patients with severe heart failure,
renal artery stenosis, pre-existing renal disorders or volume depletion (see WARNINGS AND
PRECAUTIONS).
Hyperkalaemia is most likely to occur in patients with renal impairment and those taking
potassium sparing diuretics or potassium supplements.
The events of cerebral ischaemia, transient ischaemic attack and ischaemic stroke reported
rarely in association with ACE inhibitors may be related to hypotension in patients with
underlying cerebrovascular disease. Similarly, myocardial ischaemia may be related to
hypotension in patients with underlying ischaemic heart disease.
Headache is a commonly reported adverse event, although the incidence of headache is greater in
patients receiving placebo than in those receiving ACE inhibitors.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction
rates observed in the clinical trials may not reflect the rates observed in practice and
should not be compared to the rates in the clinical trials of another drug. Adverse drug
reaction information from clinical trials is useful for identifying drug-related adverse
events and for approximating rates.
INHIBACE (cilazapril) has been evaluated for safety in 5,450 patients treated for essential
hypertension and 1,106 patients treated for congestive heart failure.
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Of these, 2,586 hypertensive and 900 congestive heart failure patients were treated with
INHIBACE in controlled clinical trials. INHIBACE was evaluated for long-term safety in 798
hypertensive and 264 congestive heart failure patients treated for one year or longer.
The most serious adverse reactions reported in the 5,450 patients treated with INHIBACE for
hypertension included: angioedema/face edema (0.1%) (see WARNINGS AND
PRECAUTIONS, Cardiovascular, Angioedema), postural hypotension (0.3%), orthostatic
hypotension (2.1%), myocardial infarction (0.1%), cerebrovascular disorder (0.04%), renal
failure (0.09%), and thrombocytopenic purpura (0.02%).
In the 1,106 patients treated with INHIBACE for congestive heart failure, the most serious
adverse reactions were: postural hypotension (1.6%), symptomatic hypotension (1.2%),
myocardial infarction (0.3%), renal failure (0.1%) (see WARNINGS AND PRECAUTIONS,
Renal), and cardiogenic shock (1 patient) (see WARNINGS AND PRECAUTIONS,
Cardiovascular, Hypotension).
Two elderly male patients, with a history of previous myocardial infarctions, on high
diuretic dosage (240 mg and 120 mg of furosemide daily, respectively) for congestive heart
failure NYHA Class III died within 8 hours after the addition of a single dose of 2.5 mg of
INHIBACE (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).
Hypotension and syncope, each reported in 0.1% of the hypertensive patients treated with
INHIBACE, were reported in 2.1% and 0.8% of the congestive heart failure patients treated with
INHIBACE.
Discontinuation of therapy was required in 63 (2.4%) of the hypertensive patients and 143
(12.9%) of the congestive heart failure patients.
See Table 1 for the most frequent adverse reactions reported in controlled clinical trials (> 1%
and more frequent than in placebo treated patients).
Table 1
The Most Frequent Adverse Reactions in Controlled Clinical
Trials (> 1% and More Frequent than in Placebo Treated
Patients)
Hypertension
n=2586
Congestive Heart Failure
n=900
headache
5.1%
3.2%
dizziness
3.0%
8.2%
fatigue
2.1%
2.6%
Page 14 of 52
cough
1.8%
7.5%
nausea
1.3%
2.9%
asthenia
0.3%
1.6%
palpitation
0.2%
1.2%
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Other adverse reactions occurring in less than 1% of the 5,450 hypertension patients and the
1,106 congestive heart failure patients treated with INHIBACE were:
Cardiovascular: Chest pain, angina pectoris, tachycardia, atrial fibrillation, arrhythmia,
flushing.
In the patient population treated with INHIBACE for congestive heart failure, there were reports
of bradycardia, AV block, extra systoles, cardiac failure and cardiac decompensation.
Renal: Micturition frequency, polyuria, dysuria, uremia, renal pain.
Hematologic: Epistaxis, anemia, purpura.
Gastrointestinal: Dyspepsia, abdominal pain, diarrhea, constipation, vomiting, flatulence, GI
bleeding, rectum bleeding, anorexia.
Dermatologic/Allergic: Rash (includes maculo-papular rash and erythematous rash), dermatitis,
pruritus, urticaria, angioedema (including face edema).
Nervous System: Increased sweating, paresthesia, hypoesthesia, impotence, decreased libido,
depression, anxiety, dry mouth, vertigo, migraine, tremor, dysphonia, ataxia, confusion,
somnolence, insomnia, nervousness.
Musculoskeletal: Myalgia, leg cramps, arthralgia.
Special Senses: Tinnitus, abnormal vision, photophobia, conjunctivitis, taste perversion.
Respiratory: Rhinitis, sinusitis, pharyngitis, bronchitis, respiratory tract infection, dyspnea,
bronchospasm.
In the congestive heart failure patient database the overall incidence of dyspnea was 3.1%.
Dyspnea however was less frequent after INHIBACE than after placebo.
Metabolic: Gout.
Page 15 of 52
Body as a Whole: Malaise, hot flushes, pain, edema, rigors.
Abnormal Hematologic and Clinical Chemistry Findings
Hematology:
Patients had clinically relevant changes in platelet (0.4% and 0.7%), neutrophil (1.9% and 1.4%)
or white blood cell counts (1.3% and 0.7%) while treated for hypertension and congestive heart
failure respectively.
Leucopenia and neutropenia: Leucopenia was observed in 0.2% (10/3,580) and 0% (0/1,163)
and neutropenia in 0.4% (22/5,720) and 0.6% (7/1,163) of the hypertensive and congestive heart
failure patients respectively. Most of these were single transient occurrences; one case with two
successive abnormalities showed no associated clinical symptoms.
Liver Function Tests:
Clinically relevant changes in the values associated with liver function (SGOT, SGPT, GGTP,
LDH, total bilirubin and alkaline phosphatase) occurred in 0.1% (bilirubin) to 1.1% (SGPT,
GGTP) of the hypertensive patients and in 0.8% (LDH) to 2.9% (SGPT) of the congestive heart
failure patients. Most of these abnormalities were transient. See WARNINGS AND
PRECAUTIONS, Hepatic, Patients with Impaired Liver Function.
Renal:
Clinically relevant changes in renal function test results (BUN or serum creatinine
concentrations) occurred in 0.6% or less of the hypertensive patients and in 2.6% and 0.9%
respectively of the congestive heart failure patients.
Hyperkalemia: (see WARNINGS AND PRECAUTIONS)
Creatinine: Serum creatinine values > 2 mg/dL were reported in 1.3% (44/3,468) of the
hypertensive patients. Two thirds of these patients had renal impairment at baseline. Serum
creatinine values >2.8 mg/dL were reported in 0.4% (5/1,163) of the congestive heart failure
patients. Of these, four of the five had abnormal serum creatinine values at baseline.
Proteinuria (>2+ dipstick reaction or excretion of > 1 g/24h): Proteinuria considered remotely,
possibly or probably related to therapy was reported in 0.5% (17/3,421) of the hypertensive
patients. Five patients had prior renal impairment. In congestive heart failure patients, 1.4%
(16/1,106) experienced potentially clinically relevant proteinuria.
Page 16 of 52
Other: In congestive heart failure patients, hyperglycemia considered remotely, possibly or
probably related to therapy was reported in 0.2% ( 2/1,106) patients.
Post-Market Adverse Drug Reactions
INHIBACE is usually well tolerated. In most cases, side effects are transient, mild or moderate
in degree, and do not require discontinuation of therapy. The most common adverse effects
include dry cough, rash, hypotension, dizziness, fatigue, headache, and nausea, dyspepsia and
other gastrointestinal disturbances.
The following adverse reactions have been seen in association with cilazapril and/or other ACE
inhibitors.
Frequency categories are as follows:
Very common ≥ 1/10
Common
≥ 1/100 and < 1/10
Uncommon ≥ 1/1,000 and < 1/100
Rare
< 1/1,000
Blood and lymphatic systems disorders
Blood disorders have been reported with ACE Inhibitors and include neutropenia and
agranulocytosis (especially in patients with renal failure and those with collagen vascular
disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia, and
hemolytic anemia.
Rare: Neutropenia, agranulocytosis, thrombocytopenia, anemia
Cardiac disorders
Pronounced hypotension may occur at the start of therapy with ACE inhibitors, particularly in
patients with heart failure and in sodium- or volume depleted patients. Myocardial infarction and
stroke have been reported and may relate to severe falls in blood pressure in patients with
ischaemic heart disease or cerebrovascular disease. Other cardiovascular effects that have
occurred include tachycardia, palpitations, and chest pain.
Uncommon: Angina pectoris, tachycardia, palpitations
Rare: Myocardial infarction
Vascular disorders
Common: Dizziness
Page 17 of 52
Uncommon: Hypotension (sometimes severe, see WARNINGS AND PRECAUTIONS)
Symptoms of hypotension may include syncope, weakness, dizziness and visual impairment.
Respiratory, thoracic and mediastinal disorders
Common: Cough (sometimes severe)
Gastrointestinal disorders
As for other ACE inhibitors, isolated cases of pancreatitis, in some cases fatal, have been
reported in patients treated with INHIBACE.
Common: Nausea
Rare: Pancreatitis
Hepatobiliary disorders
Rare: Abnormal liver function test including transaminases, bilirubin, alkaline phosphatase,
gamma GT) and cholestatic hepatitis with or without necrosis.
Immune system disorders
As with other ACE inhibitors, angioneurotic edema has been reported, although rarely, in
patients receiving INHIBACE. Since this syndrome can be associated with laryngeal edema,
INHIBACE should be discontinued and appropriate therapy instituted without delay when
involvement of the face, lips, tongue, glottis and/or larynx occurs.
Uncommon: Angioedema (may involve the face, lips, tongue, larynx or gastrointestinal tract) (see
WARNINGS AND PRECAUTIONS).
Rare: Anaphylaxis (see WARNINGS AND PRECAUTIONS), Lupus-like syndrome (symptoms
may include vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies, increased
erythrocyte sedimentation rate, eosinophilia and leukocytosis).
Nervous system disorders
Common: Headache
Uncommon: Dysgeusia
Rare: Transient ischaemic attack, ischaemic stroke (may be related in some cases to hypotension
in patients with underlying cerebrovascular disease.)
Skin and subcutaneous tissue disorders
Skin rashes (including pemphigus, Stevens-Johnson syndrome, erythema multiforme, and toxic
epidermal necrolysis) may occur; photosensitivity, alopecia, and other hypersensitivity reactions
have also been reported.
Page 18 of 52
Uncommon: Rash
Rare: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema multiforme,
pemphigus, bullous pemphigoid, exfoliative dermatitis, psoriaform dermatitis, psoriasis
(exacerbation), lichen planus, urticaria, vasculitis/purpura, photosensitivity reactions, alopecia,
onycholysis.
Renal and urinary disorders
Cases of acute renal failure have been reported in patients with severe heart failure, renal artery
stenosis or renal disorders (see WARNINGS AND PRECAUTIONS: Renal Impairment).
Rare: Renal impairment, acute renal failure, blood creatinine increased, blood urea increased,
hyperkalemia, hyponatremia (see WARNINGS AND PRECAUTIONS, Renal).
General disorders and administration site conditions
Common: Fatigue
Hypotension may occur when starting treatment or increasing dose, especially in at-risk patients
(see WARNINGS AND PRECAUTIONS). Symptoms of hypotension may include syncope,
weakness, dizziness and visual impairment.
Renal impairment and acute renal failure are more likely in patients with severe heart failure,
renal artery stenosis, pre-existing renal disorders or volume depletion (see WARNINGS AND
PRECAUTIONS).
Hyperkalemia is most likely to occur in patients with renal impairment and those taking
potassium sparing diuretics or potassium supplements.
The events of transient ischemic attack and ischemic stroke reported rarely in association with
ACE inhibitors may be related to hypotension in patients with underlying cerebrovascular
disease. Similarly, myocardial ischemia may be related to hypotension in patients with
underlying ischemic heart disease.
DRUG INTERACTIONS
Drug-Drug Interactions
Proper Name
Agents increasing
serum potassium
Ref.
CT,
C
Effect
Hyperkalemia may occur in some
patients treated with INHIBACE.
Clinical comment
Therefore, the combination
of cilazapril with agents
Page 19 of 52
Proper Name
(potassium sparing
diuretics, potassium
supplements or
potassium-containing
salt substitutes)
Ref.
Effect
Potassium sparing diuretics (e.g.
spironolactone, triamterene, or
amiloride), potassium supplements,
or potassium-containing salt
substitutes may lead to significant
increases in serum potassium
impairment (see ACTION AND
CLINICAL PHARMACOLOGY
and WARNINGS AND
PRECAUTIONS).
Antidiabetics
CT*
Concomitant administration of
ACE inhibitors and antidiabetic
medicines (insulins, oral
hypoglycaemic agents) may cause
an increased blood-glucoselowering effect with risk of
hypoglycemia.
This phenomenon appeared to be
more likely to occur during the first
weeks of combined treatment and
in patients with renal impairment.
CT,
CT*
Concomitant use of ACE
inhibitors with DPP-IV inhibitors
may lead to an increased risk for
angioedema.
Concomitant administration with
ACE inhibitors may lead to
an increased risk of hematological
reactions.
No pharmacodynamic or
pharmacokinetic interactions (and
no increase in plasma digoxin
concentrations) were observed
Allopurinol,
immunosuppressants,
and steroid medicines
T
Digoxin
CT
Clinical comment
increasing serum
potassium (potassium
sparing diuretics,
potassium supplements or
potassium-containing salt
substitutes) is not
recommended (see
WARNINGS AND
PRECAUTIONS). If
concomitant use is
indicated severe
hyperkalemia may occur
they should be used with
caution and with frequent
monitoring of serum
potassium.
Close monitoring of blood
glucose levels is advised.
See WARNINGS AND
PRECAUTIONS,
Cardiovascular,
Angioedema
Increased likelihood of
hematological reactions.
Page 20 of 52
Proper Name
Ref.
Diuretic therapy
(thiazide or loop
diuretics)
CT
Gold
C
Lithium Salts
CT
Effect
when cilazapril therapy (5 mg
once daily) was administered to
healthy volunteers receiving
digoxin (0.25 mg twice daily).
Patients concomitantly taking
ACE inhibitors and diuretics, and
especially those in whom diuretic
therapy was recently instituted,
may occasionally experience an
excessive reduction of blood
pressure after initiation of therapy.
Nitritoid reactions (symptoms
include facial flushing, nausea,
vomiting and hypotension) have
been reported rarely in patients on
therapy with injectable gold
(sodium aurothiomalate) and
concomitant ACE inhibitor therapy.
Reversible increases in serum
lithium concentrations have been
reported during concomitant
administration of lithium with
ACE inhibitors. Concomitant use
of thiazide diuretics may increase
Clinical comment
The possibility of
hypotensive effects after
the first dose of
INHIBACE can be
minimized by either
discontinuing the diuretic,
or increasing the salt
intake prior to initiation of
treatment with
INHIBACE. If it is not
possible to discontinue the
diuretic, the starting dose
of INHIBACE should be
reduced and the patient
should be closely
observed for several hours
following the initial dose
and until blood pressure
has stabilized (see
WARNINGS AND
PRECAUTIONS and
DOSAGE AND
ADMINISTRATION).
Use with caution when
INHIBACE is
coadministered with gold
salts.
Lithium should generally
not be given with ACE
inhibitors. Use of
cilazapril with lithium is
not recommended, but if
the combination proves
Page 21 of 52
Proper Name
Ref.
Non-steroidal antiinflammatory
medicinal products
(NSAIDs) including
aspirin  3 g/day
CT
Effect
the risk of lithium toxicity and
enhance the already increased risk
of lithium toxicity with ACE
inhibitors.
Lithium toxicity, including CNS
symptoms, ECG changes and renal
failure, has occurred in patients
taking ACE inhibitors. Proposed
mechanisms include decreased
renal elimination of lithium due to
decreased aldosterone secretion or
decreased renal function.
When ACE inhibitors, including
INHIBACE, are administered
simultaneously with non-steroidal
anti-inflammatory drugs (i.e.
acetylsalicylic acid at antiinflammatory dosage regimens,
COX-2 inhibitors and non-selective
NSAIDs), attenuation of the
antihypertensive effect may occur.
Concomitant use of ACE
inhibitors, including INHIBACE,
and NSAIDs may lead to an
increased risk of worsening of renal
function, including possible acute
renal failure, and an increase in
serum potassium, especially in
patients with poor pre-existing
renal function.
The introduction of therapy with
cilazapril (2.5 mg once daily) in
hypertensive patients receiving
indomethacin (50 mg twice daily)
did not result in a reduction in
blood pressure. However, the
introduction of therapy with
indomethacin (50 mg twice daily)
in hypertensive patients receiving
cilazapril (2.5 mg once daily) did
Clinical comment
necessary, careful and
frequent monitoring of
serum lithium levels
should be performed.
The combination should be
administered with caution,
especially in the elderly.
Patients should be
adequately hydrated and
consideration should be
given to monitoring for
signs of worsening heart
failure or renal function or
loss of blood pressure
control after initiation of
concomitant therapy, and
periodically thereafter.
Page 22 of 52
Proper Name
Ref.
Other antihypertensive
agents
CT
Effect
not attenuate the blood pressure
lowering effects of cilazapril. The
interaction does not appear to
occur in patients treated with
cilazapril prior to the
administration of a NSAID. There
was no evidence of a
pharmacokinetic interaction
between cilazapril and
indomethacin.
An additive effect may be
observed when INHIBACE is
administered in combination with
other blood pressure-lowering
agents (e.g., diuretics, betaadrenergic blocking drugs).
Agents affecting sympathetic
activity (e.g., ganglionic blocking
agents or adrenergic neuron
blocking agents) should be used
with caution.
Tricyclic
C
antidepressants/antipsy
chotics/anesthetics/nar
cotics
Dual blockade of the
Renin-AngiotensinSystem (RAS) with
ACE inhibitors,
ARBs or aliskirencontaining
CT
Sympathomimetics may reduce the
antihypertensive effects of ACE
inhibitors.
Concomitant use of anesthetics
during the course of general
anesthesia, as well as tricyclic
antidepressants and antipsychotics
with ACE inhibitors may result in
further reduction of blood pressure
(see WARNINGS AND
PRECAUTIONS).
Dual Blockade of the ReninAngiotensin-System (RAS) with
ACE inhibitors, ARBs or aliskiren
containing
drugs is contraindicated in
patients with diabetes and/or renal
Clinical comment
These drugs should be
introduced at a low initial
dosage, and used with
caution.
Close monitoring of blood
pressure is advised and
dose/regimen adjustment
should be considered if
necessary.
Close monitoring of blood
pressure is advised and
dose/regimen adjustment
should be considered if
necessary.
See
CONTRAINDICATIONS
and WARNINGS AND
PRECAUTIONS,
Dual Blockade of the
Renin- AngiotensinPage 23 of 52
Proper Name
drugs
Ref.
mTOR inhibitors
C,
RCS
Effect
impairment, and is generally not
recommended in other patients,
since
such treatment has been associated
with an increased incidence of
severe hypotension, renal failure,
and hyperkalemia.
Concomitant use of ACE
inhibitors with mTOR inhibitors
may lead to an increased risk for
Angioedema.
Clinical comment
System (RAS).
See WARNINGS AND
PRECAUTIONS,
Cardiovascular,
Angioedema
Legend: C = Case Study; RCS = Retrospective Cohort Study; CT = Clinical Trial; T =
Theoretical, CT*: Epidemiological studies.
Page 24 of 52
DOSAGE AND ADMINISTRATION
Dosing Considerations
Dosage of INHIBACE (cilazapril) must be individualized.
Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent
of blood pressure elevation, salt restriction, and other pertinent clinical factors. The dosage of
other antihypertensive agents being used with INHIBACE may need to be adjusted.
The dose should always be taken at about the same time each day.
Recommended Dose and Dosage Adjustment
Hypertension:
Monotherapy:
The recommended initial dose of INHIBACE is 2.5 mg once daily. Dosage should be adjusted
according to blood pressure response, generally, at intervals of at least two weeks. The usual
dose range for INHIBACE is 2.5 to 5 mg once daily. Minimal additional blood pressure lowering
effects were achieved with a dose of 10 mg once daily. A dose of 10 mg should not be exceeded.
In most patients, the antihypertensive effect of INHIBACE is maintained with a once a day
dosing regimen. In some patients treated once daily, the antihypertensive effect may diminish
toward the end of the dosing interval. This can be evaluated by measuring blood pressure just
prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is
not, either twice daily administration with the same total daily dose, or an increase in dose should
be considered. If blood pressure is not adequately controlled with INHIBACE alone a
non-potassium-sparing diuretic may be administered concomitantly. After the addition of a
diuretic, it may be possible to reduce the dose of INHIBACE.
Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, salt and/or
volume depletion, cardiac decompensation or severe hypertension) may experience an excessive
drop in blood pressure following the initial dose. A lower starting dose of 0.5 mg once daily is
recommended in such patients and the initiation of treatment should take place under medical
supervision.
Concomitant Diuretic Therapy:
In patients receiving diuretics, INHIBACE therapy should be initiated with caution, since they
are usually volume depleted and more likely to experience hypotension following ACE
inhibition. Whenever possible, all diuretics should be discontinued two to three days prior to the
administration of INHIBACE to reduce the likelihood of hypotension (see WARNINGS AND
PRECAUTIONS). If this is not possible because of the patient’s condition, INHIBACE should
Page 25 of 52
be started at 0.5 mg once daily and the blood pressure closely monitored after the first dose until
stabilized. Thereafter, the dose should be adjusted according to individual response.
Dosage in Elderly Patients (Over 65 Years)
INHIBACE treatment should be initiated with 1.25 mg (half of a 2.5 mg tablet) once daily or
less, depending on the patient’s volume status and general condition. Thereafter, the dose of
INHIBACE must be adjusted according to individual tolerability, response, and clinical status.
Dosage Adjustment in Renal Impairment
(see WARNINGS AND PRECAUTIONS, Immune, Anaphylactoid Reactions during Membrane
Exposure)
See Table 2 for the dose schedules recommended in patients with hypertension.
Table 2
Recommended Dosage Schedule for Patients with Hypertension and
Renal Impairment
Initial Dose of INHIBACE
Maximal Dose of
INHIBACE
> 40 mL/min
1 mg once daily
5 mg once daily
10-40 mL/min
0.5 mg once daily
2.5 mg once daily
Creatinine Clearance
< 10 mL/min
Not recommended.
Dosage Adjustment in Hepatic Impairment
In patients with liver cirrhosis (but without ascites) who require therapy for hypertension, cilazapril
should be dosed with great caution not exceeding 0.5 mg/day accompanied by a careful monitoring
of the blood pressure, because severe hypotension may occur. In patients with ascites, cilazapril
administration is not recommended (see WARNINGS AND PRECAUTIONS).
Congestive Heart Failure
INHIBACE can be used as adjunctive therapy with digitalis and/or diuretics in patients with
congestive heart failure. Therapy should be initiated under close medical supervision. Blood
pressure and renal function should be monitored both before and during treatment with
INHIBACE because severe hypotension and more rarely, renal failure have been reported (see
WARNINGS and PRECAUTIONS).
Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe
salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning
Page 26 of 52
treatment, to reduce the likelihood of hypotension. Serum potassium should also be monitored
(see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS).
Therapy with INHIBACE should be initiated with a recommended starting dose of 0.5 mg once
daily under close medical supervision. In elderly patients with congestive heart failure on
high diuretic dosage the recommended starting dose of INHIBACE 0.5 mg must be strictly
followed (see WARNINGS AND PRECAUTIONS).
The dose should be increased to the lowest maintenance dose of 1 mg daily, usually within a 5
day period, according to tolerability and clinical status. Further titration within the usual
maintenance dose of 1 mg to 2.5 mg daily should be carried out based on patients response,
clinical status and tolerability.
The usual maximum dose is 2.5 mg once daily. A few patients have been titrated to 5 mg once
daily with some additional benefits being achieved. However only limited data is available in
congestive heart failure patients treated with 5 mg once daily.
Dosage Adjustment in Patients with Congestive Heart Failure and Renal Impairment or
Hyponatremia:
Reduced dosage may be required for patients with congestive heart failure and renal impairment
or hyponatremia depending on the creatinine clearance. See Table 3 below.
Table 3
Recommended Dosage Schedule for Patients with Congestive Heart Failure and
Renal Impairment or Hyponatremia
Creatinine Clearance
Initial Dose of INHIBACE
Maximal Dose of INHIBACE
> 40 mL/min
0.5 mg once daily
2.5 mg once daily
10-40 mL/min
0.25 - 0.5 mg once daily
< 10 mL/min
2.5 mg once daily
Not recommended.
OVERDOSAGE
Limited data are available with regard to overdosage in humans. Symptoms associated with
overdosage of ACE inhibitors may include hypotension, which may be severe, circulatory shock,
electrolyte disturbances including hyperkalaemia and hyponatraemia, renal impairment with
metabolic acidosis, renal failure, hyperventilation, tachycardia, palpitations, bradycardia,
dizziness, anxiety and cough.
The recommended treatment of overdosage is intravenous infusion of sodium chloride 9 mg/ml
(0.9%) solution. If hypotension occurs, the patient should be placed in the shock position. If
Page 27 of 52
available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be
considered. Specific therapy with angiotensinamide may be considered if conventional therapy is
ineffective.
Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes
and creatinine concentrations should be monitored continuously.
Hemodialysis removes cilazapril and cilazaprilat from the general circulation to a limited extent.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action / Pharmacodynamics
INHIBACE (cilazapril) is an angiotensin converting enzyme (ACE) inhibitor, which is used in
the treatment of hypertension and congestive heart failure.
INHIBACE suppresses the renin-angiotensin-aldosterone system and thereby reduces both
supine and standing systolic and diastolic blood pressures. Renin is an enzyme that is released by
the kidneys into the circulation to stimulate the production of angiotensin I, an inactive
decapeptide. Angiotensin I is converted by angiotensin converting enzyme (ACE) to
angiotensin II, a potent vasoconstrictor. Angiotensin II also stimulates aldosterone secretion,
leading to sodium and fluid retention. After absorption, cilazapril, a pro-drug, is hydrolysed to
cilazaprilat, the active metabolite, which prevents the conversion of angiotensin I to
angiotensin II by inhibition of ACE. Following the administration of INHIBACE, plasma ACE
activity is inhibited more than 90% within two hours at therapeutic doses. Plasma renin activity
(PRA) and angiotensin I concentrations are increased and angiotensin II concentrations and
aldosterone secretion are decreased. The increase in PRA comes as a result of the loss of
negative feedback on renin release caused by the reduction in angiotensin II. The decreased
aldosterone secretion may lead to small increases in serum potassium along with sodium and
fluid loss. In patients with normal renal function, serum potassium usually remains within the
normal range during INHIBACE treatment. Mean serum potassium values increased by
0.02 mEq/L in patients with a normal baseline serum creatinine and by 0.11 mEq/L in patients
with a raised serum creatinine. In patients concomitantly taking potassium-sparing diuretics,
potassium levels may rise.
ACE is identical to kininase II. Therefore, INHIBACE may interfere with the degradation of the
vasodepressor peptide bradykinin. The role that this plays in the therapeutic effects of
INHIBACE is unknown.
Page 28 of 52
Hypertension
The antihypertensive effect of INHIBACE is usually apparent within the first hour after
administration, with maximum effect observed between three and seven hours after dosing.
Supine and standing heart rates remain unchanged. Reflex tachycardia has not been observed.
Small, clinically insignificant alterations of heart rate may occur.
At recommended doses, the effect of INHIBACE in hypertensive patients and in patients with
congestive heart failure is maintained for up to 24 hours. In some patients, blood pressure
reduction may diminish toward the end of the dosage interval. Blood pressure should be assessed
after two to four weeks of therapy, and dosage adjusted if required. The antihypertensive effect
of INHIBACE is maintained during long-term therapy. No rapid increase in blood pressure has
been observed after abrupt withdrawal of INHIBACE.
The antihypertensive effect of angiotensin converting enzyme inhibitors, including INHIBACE
is generally lower in black patients than in non-blacks. Racial differences in response are no
longer evident when cilazapril is administered in combination with hydrochlorothiazide.
In hypertensive patients with moderate to severe renal impairment, the glomerular filtration rate
and renal blood flow remained in general unchanged with INHIBACE.
Congestive Heart Failure
In patients with congestive heart failure the renin-angiotensin-aldosterone and the sympathetic
nervous systems are generally activated leading to enhanced systemic vasoconstriction and to the
promotion of sodium and water retention. By suppressing the renin-angiotensin-aldosterone
system, INHIBACE improves loading conditions in the failing heart by reducing systemic
vascular resistance (afterload) and pulmonary capillary wedge pressure (preload) in patients on
diuretics and/or digitalis. The onset of action of INHIBACE occurs within 1-2 hours, reaching its
maximum effect within 2-4 hours after the first dose. The exercise tolerance of these patients
was increased and was associated with an improvement of clinical symptomatology. Patients
studied belonged primarily to New York Heart Association Class II and III. The effect of
INHIBACE on survival in patients with heart failure has not been evaluated.
Pharmacokinetics
Cilazapril is well absorbed and rapidly converted to the active form, cilazaprilat. Peak plasma
concentrations, and times to peak plasma concentrations for cilazapril and cilazaprilat following
the oral administration of 0.5 to 5 mg cilazapril are given below.
Table 4
Peak Plasma Concentrations and Times to Peak Plasma Concentrations
for Cilazapril and Cilazaprilat
Page 29 of 52
Cilazapril
Oral
Dose
(mg)
0.5
1.0
2.5
5.0
Cmax
(ng/mL)
17.0
33.9
82.7
182.0
tmax
(h)
1.1
1.1
1.1
1.0
Cilazaprilat
Cmax
(ng/mL)
5.4
12.4
37.7
94.2
tmax
(h)
1.8
1.8
1.9
1.6
Maximum plasma concentrations of cilazaprilat are reached within two hours after
administration of cilazapril.
Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE
inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the
administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg
reflective of the binding to ACE. The higher doses of cilazapril are associated with longer
duration of maximum ACE inhibition.
The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on
urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of
cilazaprilat is 19%). Ingestion of food immediately before the administration of cilazapril
reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by
one hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes
have little influence on plasma ACE inhibition.
Cilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat
after intravenous administration of 2.5 mg is 91%. Total clearance is 12.3 L/h and renal
clearance is 10.8 L/h. The total urinary recovery of cilazaprilat following the oral administration
of 2.5 mg cilazapril is 52.6%.
Half-lives for the periods 1 to 4 hours and 1 to 7 days after the intravenous administration of
2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively. These data suggest the saturable binding
of cilazaprilat to ACE. The early elimination phase corresponds to the clearance of free drug.
During the terminal elimination phase, almost all of the drug is bound to enzyme. Following the
oral administration of 0.5, 1, 2.5 and 5 mg cilazapril, terminal elimination phase half-lives for
cilazaprilat are 48.9, 39.8, 38.5 and 35.8 h respectively.
After multiple dose, daily administration of 2.5 mg cilazapril for 8 days, pharmacokinetic
parameter values for intact cilazapril after the last dose are similar to the first dose. For
cilazaprilat, peak plasma concentrations are achieved at the same time but are 30% higher after
the last dose. Trough plasma concentrations and areas under the curve are 20% higher. The
Page 30 of 52
terminal elimination phase half-life after the last dose is 53.8 h. The effective half-life of
accumulation for cilazaprilat is 8.9 h.
Special Populations and Conditions
Congestive Heart Failure: In patients with congestive heart failure the clearance of cilazaprilat
is correlated with the creatinine clearance. Thus, dosage adjustments beyond those recommended
for patients with impaired renal functions (see DOSAGE AND ADMINISTRATION,
Congestive Heart Failure) should not be necessary.
Geriatrics: Following the administration of 1 mg cilazapril to healthy elderly and young
volunteers, the elderly group experienced greater peak plasma concentrations of cilazaprilat and
areas under the curve (39% and 25%, respectively) and lower total clearance and renal clearance
(20% and 28%, respectively) than the younger volunteers.
Hepatic Insufficiency: Following the administration of 1 mg cilazapril in patients with
moderate to severe compensated liver cirrhosis, peak plasma concentrations of cilazapril and
cilazaprilat are increased (57% and 28% respectively), attained 30 minutes and 45 minutes
earlier, and total clearances are decreased (51% and 31% respectively), in comparison to healthy
subjects. The renal clearance and early and terminal elimination phase half-lives of cilazaprilat
are decreased 52%, 42% and 62% respectively.
Renal Insufficiency: In patients with renal impairment, peak plasma concentrations of
cilazaprilat, times to peak plasma concentrations, early elimination phase half-lives, areas under
the curve and 24 hour plasma concentrations all increase as creatinine clearance decreases. The
changes in these parameters are small for patients with creatinine clearances of 40 mL/min or
more. Cilazaprilat clearance (total and renal) decreases in parallel with creatinine clearance.
Cilazaprilat is not eliminated in patients with complete renal failure. Hemodialysis reduces
concentrations of both cilazapril and cilazaprilat to a limited extent.
STORAGE AND STABILITY
Store 15-30 ºC. Keep container tightly closed.
SPECIAL HANDLING INSTRUCTIONS
The release of pharmaceuticals in the environment should be minimized. Medicines should not
be disposed of via wastewater, and disposal through household waste should be avoided. Use
established ‘collection systems' if available in your location.
Page 31 of 52
DOSAGE FORMS, COMPOSITION AND PACKAGING
INHIBACE (cilazapril) is available in film-coated tablets containing:


2.5 mg cilazapril - pinkish-brown, oval shaped, single scored biconvex tablets, imprinted CIL
2,5. Available in bottles of 100 tablets and blister packs of 28 tablets.1
5 mg cilazapril - reddish-brown, oval shaped, single scored biconvex tablets, imprinted CIL
5. Available in bottles of 100 tablets and blister packs of 28 tablets.1
INHIBACE 2.5 mg and 5 mg film-coated tablets contain 2.5 mg and 5 mg anhydrous cilazapril,
as cilazapril monohydrate, respectively. Non-medicinal ingredients: the tablets also contain
lactose monohydrate, cornstarch, hydroxypropyl methylcellulose, talc, sodium stearyl fumarate
and titanium dioxide. Iron oxide is present as the colouring agent in the 2.5 mg and 5 mg tablets.
1
Blister packs are not marketed in Canada.
Page 32 of 52
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name:
cilazapril monohydrate
Chemical Name:
9(s)-[1(s)-(ethoxycarbonyl)-3- phenylpropylamino]-octahydro-10-ox
o-6H-pyridazo [1,2-a] [1,2] diazepine-1(s)-carboxylic acid
monohydrate
Structural Formula:
Molecular Formula:
C22H31N3O5•H2O
Molecular Weight:
435.52
Physical Form:
White to off-white crystalline powder
Solubility:
Water (25 ºC)
pka1, pka2:
3.3, 6.4
pH (1% suspension):
4.9
Partition Coefficient:
0.8 (octanol-pH 7.4 buffer 22 ºC)
Melting Point:
98 ºC with decomposition
0.5 g/100 mL
Page 33 of 52
DETAILED PHARMACOLOGY
In in vitro studies, using hippurylhistidylleucine as substrate, cilazaprilat, the active metabolite of
cilazapril, inhibited the activity of ACE from rabbit lung (IC50 0.97-1.93 nM), hog lung
(IC50 2.83 nM), human lung (IC50 1.39 nM), and human plasma (IC50 0.61 nM). Cilazaprilat
(20 µM) did not have any effect on a number of other porcine, bovine, or human enzymes except
E. coli dipeptidyl carboxypeptidase.
In ex vivo studies, oral administration of 0.1 and 0.25 mg/kg cilazapril to rats inhibited plasma
ACE activity by 76% and 96% respectively and 0.3-3 mg/kg significantly inhibited tissue ACE
activity in a number of arteries and veins.
In vivo, the dose of cilazapril and/or cilazaprilat required to reduce the angiotensin pressor
response by 50% are summarized in Table 5 below.
Table 5
ED50 Values for Cilazapril and/or Cilazaprilat
Animal Model
Conscious normotensive rats
Anesthetised SHAD (unilaterally adrenalectomised and
contralaterally adrenal demedulated SHR) rats
2-kidney-1-clip Goldblatt renal hypertensive rats
Anesthetised normotensive dogs
Cilazapril
Activity
ED50 0.02 mg/kg
p.o.
(at 60 min)
ED50 0.44
µmol/kg i.v.
ED50 0.043 mg/kg
i.v.
Cilazaprilat
Activity
—
ED50 0.035 mg/kg
i.v.
(0.084 µmol/kg)
—
ED50 0.06
µmol/kg i.v.
ED50 0.006
mg/kg i.v.
In the anesthetised SHAD rats 0.06 µmol/kg i.v. cilazaprilat potentiated the bradykinin induced
vasodepressor response.
Page 34 of 52
The antihypertensive activity of cilazapril was assessed in a number of experimental animal
models. In spontaneously hypertensive rats (SHR), single oral doses of 10 and 30 mg/kg
cilazapril reduced systolic blood pressure for longer than six hours. Repeated daily dosing with
oral doses of 10 and 30 mg/kg cilazapril demonstrated 24-hour activity and at the higher dose,
antihypertensive effect became maximum after one week. When administered twice daily, the
lowest oral dose of cilazapril that reduced systolic blood pressure was 1 mg/kg. Dose dependent
decreases in systolic blood pressure were observed between oral doses of 1 and 10 mg/kg twice
daily. No further increase in effect was observed with an oral dose of 30 mg/kg twice daily.
Intravenous administration of up to 10 mg/kg of either cilazapril or cilazaprilat to conscious SHR
evoked only small reductions in blood pressure. The reason for this disparity with the oral dosing
data in the same animal model is unclear.
Following the oral administration of 10 mg/kg cilazapril, the maximum decrease in systolic
arterial pressure observed in conscious renal hypertensive hypovolemic dogs was approximately
double that observed in normovolemic dogs. In the hypovolemic dogs, the systolic blood
pressure fell significantly within 30 minutes of the first dose. The effect persisted for 6 hours.
Maximum decrease in systolic arterial pressure in conscious normotensive hypovolemic dogs
was similar to that observed in renal hypotensive normovolemic dogs.
Heart rate changes accompanying the antihypertensive action of cilazapril in the rat and the dog
were minimal.
Total peripheral resistance and regional vascular resistance were reduced in all vascular beds
except in the heart in SHR administered multiple, oral, daily doses of 10 mg/kg cilazapril.
Regional blood flow to the kidneys, intestine and skin increased. Regional blood flow to the
heart decreased. No changes were observed in cardiac output, cardiac index, stroke volume or
heart rate. Hemodynamic and blood flow changes were similar after acute or repeated (twice
daily for two weeks) administration of 1 mg/kg cilazapril. Additional increases in blood flow to
the lungs, stomach, small intestine, pancreas and thymus were observed however.
In conscious dogs, cilazapril had no effect on left ventricular pressure and on force of cardiac
contraction at 3 mg/kg p.o. and marginal effects at 10 mg/kg p.o. At these doses, slight decreases
were noted in abdominal aortic blood flow and heart rate. In anesthetized dogs, intravenous
cilazapril doses of 0.03-1 mg/kg evoked dose dependent decreases in blood pressure and left
ventricular pressure. At 1 mg/kg, left ventricular end diastolic pressure was decreased 15%,
myocardial contractile force was reduced and heart rate was unchanged. At 0.3 mg/kg, cardiac
output, coronary blood flow, left ventricular minute work, left ventricular stroke work, and
cardiac index were decreased 15%, 12%, 31%, 40%, and 12% respectively. In the anesthetized
dog with ischemic heart failure, intravenous doses of cilazaprilat (0.1-1 mg/kg) reduced total
peripheral resistance, left ventricular end diastolic pressure, dp/dt, and mean aortic blood
pressure. Cardiac output, heart rate, pulmonary arterial pressure and right arterial pressure
remained unchanged.
Page 35 of 52
Oral administration of 3 mg/kg cilazapril did not have an effect on the increase in blood pressure
and heart rate accompanying exercise in conscious cats. In anesthetized cats, cilazapril
(10 mg/kg i.v.) increased right ventricular force of contraction (28%) and cardiac output (19%).
Heart rate changes were minor.
The pharmacokinetics of cilazapril and cilazaprilat have been examined in mice, rats, dogs,
monkeys, marmosets and baboons. The oral absorption of cilazapril is rapid and peak plasma
concentrations of cilazapril occur in less than 1 hour. Absorption is 70-89%. Cilazapril plasma
concentrations decline rapidly with a half-life of 0.7-2.7 hours. Plasma concentrations are less
than dose proportional in baboons, and in rats and marmoset levels are too low for reliable
quantitation.
Cilazaprilat is produced rapidly in all species and peak concentrations occur in less than 1.5
hours. Bioavailability from oral cilazapril is 70-89%. Cilazaprilat plasma concentrations decline
in a biphasic manner with half-lives of 0.5-3.5 hours and 12-68 hours. Plasma concentrations are
less than dose proportional, and show a low order of dose dependence during the terminal phase.
This is consistent with saturable binding to ACE.
The distribution of drug related material is largely confined to excretory organs, but all major
tissues are exposed, including the fetus of pregnant animals. There is no evidence of tissue
retention, and more than 95% of the dose is recovered within three days. Repeat administration
leads to some accumulation, but only in a limited number of tissues, notably the liver and kidney.
Excretion is rapid in all species. More than 90% of the total recovery in urine is achieved within
24 hours. Excretion is predominantly hepatic in rats and baboons, and renal in marmosets.
Page 36 of 52
TOXICOLOGY
Table 6
Acute Toxicity
Species
Sex
Route
Approximate LD50 (mg/kg)
Mouse
M
F
M+F
M
F
M+F
p.o.
p.o.
i.v.
i.p.
i.p.
s.c.
4,600
2,500 - <5,000
>250
1,600
1,300
>1,000
Rat
M+F
M+F
p.o.
i.p.
>4,000 - <5,000
830
Monkey
M+F
p.o.
>4,000 - <5,000
The signs of toxicity include: ataxia, reduced motor activity, diarrhea, respiratory depression,
tremors, piloerection, prostration, hunched appearance, salivation, emesis and facial fur-staining.
Page 37 of 52
Table 7
Long-Term Toxicity
1
DOSE
ADMINISTRATION
(mg/kg/day)
SPECIES
(#/group)
STUDY
DURATION
Rat
(8M + 8F)
2 Weeks
0, 2, 6, 20
i.v.
All dose groups: Swollen tails in individual rats after 8-10 days; slight
increase in urine volume (males).
Monkey
Marmoset
(3M + 3F)
2 Weeks
0, 2, 6, 20
i.v.
All dose groups: Slightly depressed heart rates.
Rat
(5M + 5F)
4 Weeks
0, 5, 15, 50
p.o.
All dose groups: Increased water consumption.
15 and 50 mg/kg/day: Minimal decreases in RBC, Hb and PCV values
(females); increase in plasma urea (2-3x).
50 mg/kg/day: Salivation (6/10) from week 2; decrease body weight gain
(20%); slight reduction in food consumption; increased incidence of
kidney tubule cells in urine (females).
Rat
(16M + 16F)
4 Weeks
25, 125, 625
p.o.
All dose groups: Salivation; slight reduction in motor activity; increased
urine volumes and minimal decreases in specific gravity (males).
125 and 625 mg/kg/day: Decreased body weight gain and food
consumption (males only at 125 mg/kg/day); slight decreases in RBC, Hb
and PCV (males); very slight thickening of glomerular afferent arteriolar
wall in the kidney (males) (1/10 - 125 mg/kg/day, 6/10 - 625 mg/kg/day).
625 mg/kg/day: Increased BUN values (1.5x) (males); decreased BMC1
(males); slight decrease in heart and liver (males) weight.
ROUTE
FINDINGS
Bone marrow nucleated cell count.
Page 38 of 52
Table 7
Long-Term Toxicity
DOSE
ADMINISTRATION
(mg/kg/day)
SPECIES
(#/group)
STUDY
DURATION
Monkey
Marmoset
(3/6M + 3F)
4 Weeks
0, 5, 15, 50
p.o.
15 and 50 mg/kg/day: Marginal decreases in RBC, Hb and PCV values.
50 mg/kg/day: Increase in plasma urea (2x), K+ and cholesterol values;
increased incidence of kidney tubule cells in urine.
Rat
(16M + 16F)
13 Weeks
0, 10, 50, 250
p.o.
All dose groups: Very slight increases in urine volume and decreased SG
values (males).
50 and 250 mg/kg/day: Dose-related decrease in body weight gain (males
only at 50 mg/kg/day); increased BUN levels (2x) (males); slight thickening of glomerular afferent arterioles in the kidneys (10/30).
250 mg/kg/day: Slight decrease in spontaneous activity and salivation;
inhibition of food consumption; small decreases in RBC and BMC
(males), and in RBC, PCV and Hb (females).
Monkey
Cynomolgus
(4M + 4F)
13 weeks
0, 2.5, 25, 50
p.o.
25 and 50 mg/kg/day: Slight decreases in RBC, Hb and PCV. Slight to
moderate hyperplasia of the juxtaglomerular apparatus; dose-related
decreased body weight gains.
50 mg/kg/day: Two deaths; salivation; emesis; decreased spontaneous
activity. Slight decrease in BMC, total protein and inorganic phosphate;
increase in BUN (4x), blood creatinine; enlargement of kidney (1 female);
reduction in heart weight; kidney tubular dilatation.
ROUTE
FINDINGS
Page 39 of 52
Table 7
Long-Term Toxicity
SPECIES
(#/group)
STUDY
DURATION
Monkey
Baboon
(2M + 2F)
13 Weeks
Rat
(30M + 30F)
26 Weeks
DOSE
ADMINISTRATION
(mg/kg/day)
ROUTE
FINDINGS
0, 2, 10, 20, 40
p.o.
All dose groups: Emesis; slight reductions in heart rate, body weight gain
and heart weight; hypertrophy and hyperplasia of the juxtaglomerular
cells (1/4 - 10 mg/kg, 3/4 - 20 mg/kg, 4/4 - 40 mg/kg).
20 and 40 mg/kg/day: Slight decrease in RBC, PCV and Hb; kidney
tubular basophilia/ dilatation (1/4 - 20 mg/kg; 3/4 - 40 mg/kg). Increased
urea (2x) in 40 mg/kg only.
0, 5, 30, 200;
0, 2, 12, 75 - from
Week 6; 0, 2, 12, 50
from Week 14
p.o.
All dose groups: Slight decrease in heart rate; weight loss; lethargy;
hunched posture. Pilo-rection; facial fur-staining; dose-related increases in
kidney weights (male).
12 and 50 mg/kg/day: Hypertrophy of afferent glomerular arterioles in
the kidneys (13 weeks).
50 mg/kg/day: Body weight gain decrease (14%) (males); increased
water intake. Increased BUN levels (3x) (males), ALP activity, and liver
weights (males); prominent kidney tubular regeneration; kidney tubular
dilatation; minimal kidney tubular necrosis (2 animals at 13 weeks).
Sclerosis (2 animals at 26 weeks).
Page 40 of 52
Table 7
Long-Term Toxicity
SPECIES
(#/group)
STUDY
DURATION
Monkey
Marmoset
(9, 7, 7, 11M+
9, 7, 7, 11F)
26 Weeks
Monkey
Baboon
(7M + 7F)
52 Weeks
DOSE
ADMINISTRATION
(mg/kg/day)
ROUTE
FINDINGS
0, 5, 30, 200;
0, 2, 15, 100 from
Week 9; 0, 2, 15, 50
from Week 14
p.o.
200 mg/kg/day: Depression in heart rate; body weight loss (females).
15 mg/kg/day: Two deaths (unrelated to treatment) of minor glomerular
arteriolar hypertrophy (13 and 26 weeks).
50 mg/kg/day: Six deaths (two unrelated to treatment); unsteadiness;
inactivity; salivation; emesis; diarrhea; slight decrease in RBC, PCV, Hb
and bone marrow, myeloid/erythroid ratio (26 weeks). Increase in plasma
urea (2x); small reductions in urine osmolality; slight kidney tubular
dilatation and tubular epithelium regeneration (4/5 at 13 weeks 100 mg/kg) (4/10 after 26 weeks).
0, 0.5, 4, 40
p.o.
4 and 40 mg/kg/day: Hyperplasia and hypertrophy of juxtaglomerular
apparatus with hypertrophy of muscle cells of glomerular arterioles (1/10
- 4 mg/kg; 8/10 - 40 mg/kg/day).
40 mg/kg/day: Emesis; body weight gain reduction; slight reduction in
RBC, PCV and Hb; increase in urea values (2x) and creatinine; osmolality
reductions; increased incidence in proteinous casts (Week 52); small
increase in adrenal and thyroid weights.
Page 41 of 52
Table 7
Long-Term Toxicity
SPECIES
(#/group)
STUDY
DURATION
Rat
(35M + 35F)
78 Weeks
DOSE
ADMINISTRATION
(mg/kg/day)
0, 0.5, 4, 40
ROUTE
p.o.
FINDINGS
All dose levels: Small reductions in body weight gain.
4 and 40 mg/kg/day: Slight decrease in RBC, PCV and Hb; minimal
reduction in food intake; increase in BUN (2x) (males).
40 mg/kg/day: Increased water consumption; slight increase in total
WBC count (males); increased urine volumes (males); irregular surface
ocysts in the kidneys (7/40 at 76 weeks); increased kidney weights
(males); slight decrease in heart and liver weight (females); vascular
hypertrophy (20/20 males, 17/20 females) consisting of glomerular
afferent arteriolar wall thickening; similar but less frequent and less
severe changes were observed in the mid dose group.
Page 42 of 52
Table 8
Reproduction and Teratology
SPECIES
#/GROUP
DOSE
(mg/kg/day)
ROUTE
DURATION OF
DOSING
EFFECTS
Fertility and General Reproduction Performance
Rat
Charles River
(Crl:CD (SD) BR)
(30M + 30F)
0, 1, 7, 50
p.o.
Males - 70 days prior
to mating and up to 14
days during mating.
Females - 14 days
before mating, during
gestation and until
Day 21 post-partum.
All dose groups: No effect on mating or fertility at any dose.
Retching reflex after dosing (dose-related) (males). Decreased
body weight gain.
Males at 50 mg/kg/day: Six deaths (due to dosing error).
Females at 50 mg/kg/day: Two deaths (50 mg/kg) (due to dosing
error). Increased preimplantation loss (forced delivery group at
50 mg/kg).
F1 generation at 7 and 50 mg/kg/day: Reduced body weight at the
end of lactation; increased incidence of dilatation of the renal
pelvis. Reduction in viable fetuses due to a lower number of
implantations (50 mg/kg).
0, 2, 30, 400
p.o.
Days 6-17 of
gestation.
All dose groups: No effect on embryonic, fetal or postnatal
development.
Females at 400 mg/kg/day: Body weight gain and food
consumption were reduced during latter half of gestation.
F1 generation at 400 mg/kg/day: Slight increase in renal
cavitation incidence.
Embryotoxicity
Rat
Charles River
(CD)
(35F)
Page 43 of 52
Table 8
Reproduction and Teratology
SPECIES
#/GROUP
DOSE
(mg/kg/day)
ROUTE
DURATION OF
DOSING
EFFECTS
Fertility and General Reproduction Performance
Monkey
Cynomolgus
(10 or 11F)
0, 20
p.o.
Days 21 to 31 or Days
32 to 45 of gestation.
Control group: Reduced food consumption and diarrhea (5/10
females); 2/10 abortions between Days 51-53 of pregnancy; low
incidence of skeletal variations in tail (2/8 fetuses) and ribs (2/8).
20 mg/kg/day - Days 21-31: Reduced food consumption (10/10
females); diarrhea (2/10); vomiting (2/10). Skeletal findings ribs (2/8 fetuses), humeri (2/8), distal caudal variations (4/8), and
prepuce not patent (2/8) - not treatment related.
20 mg/kg/day - Days 32-45: Decreased food consumption and/or
diarrhea (11/11 females); 5/11 abortions; 2/11 maternal deaths
(not treatment related). Caudal and humerus variations
(1/5 fetuses) - not treatment related.
p.o.
Day 15 of gestation to
Day 21 post-partum.
Females at 50 mg/kg/day: 5 deaths on Day 18 postcoitus or Days
4-16 of lactation (due to dosing error).
F1 generation at 50 mg/kg/day: Increased pup mortality (4.9%);
reduction in body weight gain during lactation; an associated
slight delay in pinna unfolding.
Peri- and Post-natal Toxicity
Rat
Charles River
(CDCrl:CD(SD) BR)
(25 or 30F)
0, 1, 7, 50
Page 44 of 52
CARCINOGENICITY
An eighty-eight week carcinogenicity study with cilazapril was conducted in mice initially dosed
at 5, 25 or 100 mg/kg/day, subsequently reduced to 1, 7 or 50 mg/kg/day from week 11 onwards.
Another carcinogenicity study was conducted in rats in which dose levels of 0.5, 4 or
40 mg/kg/day were administered for 104 weeks. Hypertrophy of renal afferent glomerular
arterioles and interlobular arteries, and increased cortical nephropathy were the only recorded
findings and occurred in the mid- and high-dose groups in both studies. Tri-PAs staining of
kidney sections from the 104 week rat carcinogenicity study indicated no hyperplastic or7
neoplastic oxyphilic cell response and no enhancement of the development of oncocytomas.
MUTAGENICITY
No evidence of mutagenicity with cilazapril was found in the Ames test with or without
metabolic activation (up to 2.0 mg/plate), “Treatment and Plate” test (up to 7,000 µcg/mL),
unscheduled DNA synthesis assay (up to 200 µcg/mL), mutagenic assay with Chinese hamster
V79 cells with or without metabolic activation (up to 4,800 µcg/mL), chromosomal abbreration
test with or without metabolic activation (up to 3,500 µcg/mL), or in vivo micronucleus test in
mice (2.0 g/kg).
Page 45 of 52
REFERENCES
1. Ajayi AA, Elliott HL, Reid JL. The pharmacodynamics and dose-response relationships of
the angiotensin converting enzyme inhibitor, cilazapril, in essential hypertension.
Br J Clin Pharmacol 1986;22:167-75.
2. Francis RJ, et al. Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal
volunteers and the relationship of enzyme inhibition: development of a mathematical model.
J Cardiovasc Pharmacol 1987;9:32-8.
3. Belz GG, et al. Interactions between cilazapril and propranolol in man; plasma drug
concentrations, hormone and enzyme responses, haemodynamics, agonist, dose-effect curves
and baroreceptor reflex. Br J Clin Pharmacol 1988;26:547-56.
4. Nussberger J, et al. Repeated administration of the converting enzyme inhibitor cilazapril to
normal volunteers. J Cardiovasc Pharmacol 1987;9:39-44.
5. Sanchez RA, et al. Antihypertensive, enzymatic, and hormonal activity of cilazapril, a new
angiotensin-converting enzyme inhibitor in patients with mild to moderate essential
hypertension. J Cardiovasc Pharmacol 1988;11:230-4.
6. Shionoiri H, et al. Antihypertensive effects and pharmacokinetics of single and consecutive
doses of cilazapril in hypertensive patients with normal and impaired renal function.
J Cardiovasc Pharmacol 1988;11:242-9.
7. Shionoiri H, et al. Pharmacokinetics of single and consecutive doses of cilazapril and its
depressor effects and patients with essential hypertension. Am J Hypertens 1988;1:269-73.
8. Shionoiri H, et al. Pharmacokinetics of single and consecutive doses of cilazapril and its
depressor effects in hypertensive patients with renal dysfunction. Am J Hypertens
1988;1:230-2.
9. White WB, et al. The effects of the long-acting angiotensin-converting enzyme inhibitor
cilazapril on casual, exercise, and ambulatory blood pressure. Clin Pharmacol Ther
1988;44:173-8.
10. Lacourciere Yves, et al. Antihypertensive effects of cilazapril, 2.5 and 5.0 mg, once daily
versus placebo on ambulatory blood pressure following single- and repeat-dose
administration. J CARDIOVASCPHARMACOL 1991;18(2):219-223.
11. Kobrin, I., et al. Antihypertensive duration of action of cilazapril in patients with mild to
moderate essential hypertension. Drugs 1991;27(Suppl 2):225S-234S.
12. Guntzel, P, et al. The effect of cilazapril, a new angiotensin converting enzyme inhibitor, on
peak and trough blood pressure measurements in hypertensive patients. J Cardiovasc
Pharmacol 1991;17:8-12.
Page 46 of 52
13. Sanchez, RA, et al. Effects of ACE inhibition on renal haemodynamics in essential
hypertension and hypertension associated with chronic renal failure. Drugs
1991;41(Suppl 1):25-30.
14. Tunon-de-Lara JM, et al. ACE inhibitors and anaphylactoid reactions during venom
immunotherapy. Lancet 1992;340:908.
15. Corder CN, et al. Effect of cilazapril on exercise tolerance in congestive heart failure.
Pharmacology 1993;46(3):148-54.
16. Doessegger L, et al. Comparison of the effects of cilazapril and captopril versus placebo on
exercise testing in chronic heart failure patients: a double-blind, randomized, multicenter
trial. Cardiology 1995;86(S1):34-40.
17. Drexler H, et al. Contrasting peripheral short-term and long-term effects of converting
enzyme inhibition in patients with congestive heart failure. A double-blind, placebocontrolled trial. Circulation 1989;79(3):491-502.
18. Garg R, et al. Overview of randomized trials of angiotensin-converting enzyme inhibitors on
mortality and morbidity in patients with heart failure. JAMA 1995;273(18):1450-56.
19. Kiowski W, et al. Cilazapril in congestive heart failure. A pilot study. Drugs 1991;S41(1):5461.
20. Kiowski W, et al. Coronary vasodilation and improved myocardial lactate metabolism after
angiotensin converting enzyme inhibition with cilazapril in patients with congestive heart
failure. American Heart Journal 1991;122(5):1382-88.
21. Rosenethal E, et al. A pharmacokinetic study of cilazapril in patients with congestive heart
failure. British Journal of Clinical Pharmacology 1989;27(S2):267S-273S.
22. Wiseman MN, et al. Initial and steady state pharmacokinetics of cilazapril in congestive
cardiac failure. Journal of Pharmacy and Pharmacology 1991;43(6):406-10.
Page 47 of 52
IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
Pr
INHIBACE®
cilazapril tablets
Read this carefully before you start taking INHIBACE® and
each time you get a refill. This leaflet is a summary and will
not tell you everything about INHIBACE®. Talk to your
doctor, nurse, or pharmacist about your medical condition and
treatment and ask if there is any new information about
INHIBACE®.
ABOUT THIS MEDICATION
What the medication is used for:
INHIBACE is used to treat the following:
 Mild to moderate essential high blood pressure
(hypertension). The cause of essential high blood pressure
is unknown.
 Heart failure. This is a condition where the heart cannot
pump adequate amounts of blood to satisfy the needs of
the body.
What it does:
INHIBACE is an angiotensin converting enzyme (ACE) inhibitor.
You can recognize ACE inhibitors because their medicinal
ingredient ends in ‘-PRIL’.
It works by making your blood vessels relax and widen. This helps
to lower your blood pressure. It also makes it easier for your heart
to pump blood around your body if you have chronic heart failure.
This medicine does not cure your disease. It helps to control it.
Therefore, it is important to continue taking INHIBACE regularly
even if you feel fine.
When it should not be used:
Do not take INHIBACE if you:
 Are allergic to cilazapril or to any non-medicinal
ingredient in the formulation.
 Are allergic (hypersensitive) to other ACE inhibitor
medicines. These include captopril, enalapril, lisinopril
and ramipril.
 Have experienced an allergic reaction (angioedema) with
swelling of the hands, feet, or ankles, face, lips, tongue,
throat, or sudden difficulty breathing or swallowing, to
any ACE inhibitor or without a known cause. Be sure to
tell your doctor, nurse, or pharmacist that this has
happened to you.
 Have been diagnosed with hereditary angioedema: an
increased risk of getting an allergic reaction that is passed
down through families. This can be triggered by different
factors, such as surgery, flu, or dental procedures.
 Are pregnant or intend to become pregnant. Taking
INHIBACE during pregnancy can cause injury and even
death to your baby.
 Are breastfeeding. INHIBACE passes into breast milk.
 Have a build up of fluid in your abdomen (ascites).

Are already taking a blood pressure-lowering medicine
that contains aliskiren (such as Rasilez) and you have
diabetes or kidney disease.
 Are lactose intolerant or have one of the following rare
hereditary diseases:
o Galactose intolerance
o Lapp lactase deficiency
o Glucose-galactose malabsorption
as lactose is a non-medicinal ingredient in INHIBACE®
What the medicinal ingredient is:
cilazapril
What the non-medicinal ingredients are:
lactose monohydrate, cornstarch, hydroxypropyl methylcellulose,
talc, sodium stearyl fumarate and titanium dioxide. Iron oxide is
present as the colouring agent in the tablet.
What dosage forms it comes in:
Tablets; 2.5 mg and 5.0 mg
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions - Pregnancy
INHIBACE should not be used during pregnancy. If you
discover that you are pregnant while taking INHIBACE,
stop the medication and contact your doctor, nurse, or
pharmacist as soon as possible.
BEFORE you use INHIBACE talk to your doctor, nurse or
pharmacist if you:
 Are allergic to any drug used to lower blood pressure.
 Have narrowing of an artery or a heart valve.
 Have/had a heart attack or a stroke.
 Have heart failure.
 Have diabetes, liver or kidney disease.
 Are on dialysis.
 Are on LDL apheresis (a treatment to lower the LDL
cholesterol in the blood).
 Are dehydrated or recently suffered from excessive
vomiting, diarrhea or sweating.
 Are on a low salt diet.
 Are receiving gold (sodium aurothiomalate) injections.
 Have recently received or are planning to have allergy
shots for bee or wasp stings.
 Have a collagen disease (skin disease) such as lupus
(systemic lupus erythematosus) or scleroderma (a skin
condition leading to hardening or thickening of the skin).
 Are less than 18 years old. INHIBACE is not
recommended for use in children.
 Are taking a medicine that contains aliskiren, such as
Rasilez, used to lower high blood pressure. The
combination with INHIBACE is not recommended.
 Are taking an angiotensin receptor blocker (ARB). You
can recognize an ARB because its medicinal ingredient
ends in “-SARTAN”.
If any of the above apply to you, or if you are not sure, talk to
your doctor or pharmacist before you take INHIBACE.
Page 48 of 52
IMPORTANT: PLEASE READ
You may become sensitive to the sun while taking INHIBACE®.
Exposure to sunlight should be minimized until you know how you
respond.
If you are going to have surgery and will be given an anesthetic, be
sure to tell your doctor or dentist that you are taking INHIBACE®.
Driving and using machines
You may feel dizzy while taking INHIBACE. This is more likely
to happen when you first start treatment or when the dose is
increased. If you feel dizzy, do not drive or use any tools or
machines.
INTERACTIONS WITH THIS MEDICATION
As with most medicines, interactions with other drugs are possible.
Tell your doctor, nurse, or pharmacist about all the medicines you
take, including drugs prescribed by other doctors, vitamins,
minerals, natural supplements, or alternative medicines.
The following may interact with INHIBACE:














Agents increasing serum potassium, such as a salt
substitute that contains potassium, potassium supplements
or potassium-sparing diuretics (a specific kind of “water
pill,” e.g. spirolactone, triamterene, amiloride,
eplerenone).
Allopurinol used to treat gout.
Anesthetics and narcotics (for pain relief)
Antipsychotics (for treatment of schizophrenia or bipolar
disorder)
Anti-diabetic drugs including insulin and oral medicines
(e.g. metformin, gliptins, sulfonylureas).
Digoxin, a heart medication
Gold salts (for the treatment of rheumatoid arthritis).
Lithium (used to treat bipolar disorder).
Non-steroidal anti-inflammatory drugs’ (NSAIDs), used
to reduce pain and swelling. Examples include aspirin,
indometacin, naproxen, ibuprofen and celecoxib.
Other blood pressure lowering drugs, including diuretics
(“water pills”), aliskiren-containing products (e.g.
RASILEZ), angiotensin receptor blockers (ARBs) or
other ACE inhibitors (in addition to INHIBACE).
Steroid medicines (such as hydrocortisone, prednisolone
and dexamethasone) or other medications which suppress
the immune system.
Tricyclic antidepressants (e.g. amitriptyline,
clomipramine, imipramine)
mTOR inhibitors (e.g. sirolimus, everolimus)
DPP-IV inhibitors (e.g. vildagliptin)
PROPER USE OF THIS MEDICATION
Take INHIBACE exactly as prescribed. It is recommended to take
your dose at about the same time every day.
Usual Adult Dose:
Follow your doctor’s instructions about how much medicine you
should take. If you have any questions, you should consult your
doctor or pharmacist.
Overdose:
If you think you have taken too much INHIBACE contact your
doctor, nurse, pharmacist, hospital emergency department or
regional Poison Control Centre immediately, even if there are
no symptoms.
If you take more INHIBACE than you should, the following
effects may happen: feeling dizzy or light-headed, shallow
breathing, cold clammy skin, being unable to move or speak and a
slow heart beat.
Missed Dose:
If you forget to take a dose, skip the missed dose. Then take the
next dose when it is due.
Do not take a double dose (two doses at the same time) to make
up for a forgotten dose.
If you have any further questions on the use of this product, ask
your doctor or pharmacist.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM

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

Dizziness, headache, trouble sleeping
Drowsiness, feeling tired, weakness
Runny or blocked nose, sneezing
Rash, itching
Abdominal pain, upset stomach, decreased appetite
Diarrhea, constipation, nausea, vomiting
Muscle cramps and/or joint pain, pins and needles
sensation
Sweating more than usual, flushing
If any of these affects you severely, tell your doctor, nurse or
pharmacist.
INHIBACE can cause abnormal blood test results. Your doctor
will decide when to perform blood tests and will interpret the
results.
Taking INHIBACE with food and drink
Tell your doctor or pharmacist if you are taking food supplements
that contain potassium.
Page 49 of 52
IMPORTANT: PLEASE READ
SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN
AND WHAT TO DO ABOUT THEM
Symptom / effect
Talk with your
doctor or
pharmacist
Only if
severe
Common
(affects less
than 1 in 10
people)
Uncommon
(affects less
than 1 in
100 people)
Low Blood
Pressure:
Dizziness,
fainting,
lightheadedness.
May occur when
you go from
sitting to
standing up.
Increased levels
of potassium in
the blood:
Irregular
heartbeat,
muscle
weakness and
generally feeling
unwell.
Angioedema
and Severe
Allergic
Reactions
(anaphylaxis):
Swelling of the
face, eyes, lips,
tongue or throat,
difficulty
swallowing or
breathing, rash
(including skin
rash which may
be severe),
hives, itching,
fever, abdominal
cramps, chest
discomfort or
tightness.
Electrolyte
Imbalance:
weakness,
drowsiness,
muscle pain or
cramps, irregular
heartbeat
Increased heart
rate
Chest pain
(Angina)
In all
cases

Stop
taking
drug and
seek
immediate
emergency
medical
help
SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN
AND WHAT TO DO ABOUT THEM
Symptom / effect
Talk with your
doctor or
pharmacist
Only if
severe
 (if actual
fainting
occurs)
Rare
(affects less
than 1 in
1000
people)
In all
cases
Breathing
problems,
including
shortness of
breath and
tightness in the
chest.
Decreased
platelets:
bruising,
bleeding, fatigue
and weakness.
Stop
taking
drug and
seek
immediate
emergency
medical
help








Decreased
white blood
cells:
Infections (e.g.,
sore throat,
fever), fatigue,
aches, pains,
and flu-like
symptoms.
Stroke:
weakness,
blurred vision
slurred speech,
trouble
speaking, face
drooping,
dizziness,
headache.




Page 50 of 52
IMPORTANT: PLEASE READ
SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN
AND WHAT TO DO ABOUT THEM
Symptom / effect
Talk with your
doctor or
pharmacist
Only if
severe
Heart attack:
chest pain and
pressure (can be
radiating from
the left arm),
heart
palpitations,
nausea,
vomiting,
trouble
breathing,
sweating,
anxiety.
Irregular
heartbeat
Lupus-like
Syndrome:
fever, fatigue,
joint and muscle
pain, generally
feeling unwell.
Liver
Disorder:
Yellowing of
the skin or eyes,
dark urine,
abdominal pain,
nausea,
vomiting, loss
of appetite.
Inflammation
of the
Pancreas:
abdominal pain
that lasts and
gets worse when
you lie down,
nausea,
vomiting.
In all
cases
Stop
taking
drug and
seek
immediate
emergency
medical
help



Symptom / effect
Talk with your
doctor or
pharmacist
Only if
severe
Kidney
Disorder:
Change in
frequency of
urination,
nausea,
vomiting,
swelling of
extremities,
fatigue.
In all
cases
Stop
taking
drug and
seek
immediate
emergency
medical
help









SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN
AND WHAT TO DO ABOUT THEM
Serious skin
reactions
(StevensJohnson
Syndrome,
Toxic
Epidermal
Necrolysis):
Any
combination of
itchy skin rash,
redness,
blistering
and severe
peeling of the
skin and/or
inside
of the lips, eyes,
mouth, nasal
passages or
genitals,
accompanied by
fever, chills,
headache,
cough,
body aches or
swollen glands,
joint pain,
yellowing of the
skin or eyes,
dark urine.

This is not a complete list of side effects. For any unexpected
effects while taking INHIBACE, contact your doctor or
Page 51 of 52
IMPORTANT: PLEASE READ
pharmacist.
Hoffmann-La Roche Limited
Mississauga, Ontario L5N 5M8
If you have any further questions, ask your doctor or pharmacist.
HOW TO STORE IT
Store 15-30 ºC. Keep container tightly closed.
Keep out of reach and sight of children.
Medicines should not be disposed of via wastewater or household
waste. Ask your pharmacist how to dispose of medicines no longer
required. These measures will help to protect the environment.
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions associated with
the use of health products to the Canada Vigilance Program by
one of the following 3 ways:
-------------------------------------------------------------------------
Report online at www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form and:
- Fax toll-free to 1-866-678-6789, or
- Mail to: Canada Vigilance Program
Health Canada
Postal Locator 0701E
Ottawa, Ontario
K1A 0K9
Postage paid labels, Canada Vigilance Reporting Form
and the adverse reaction reporting guidelines are
available on the MedEffect™ Canada Web site at
www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to the management
of side effects, contact your health professional. The Canada
Vigilance Program does not provide medical advice.
MORE INFORMATION
This document plus the full product monograph, prepared for
health professionals can be found at:
http://www.rochecanada.com
or by contacting the sponsor, Hoffmann-La Roche Limited, at:
1-888-762-4388 (Drug Information).
This leaflet was prepared by Hoffmann-La Roche Limited.
Last revised: March 12, 2015
 Copyright 1993 - 2015 Hoffmann-La Roche Ltd
INHIBACE is a registered trade-mark of Hoffmann-La Roche
Limited, used under license.
All other trade-marks are the property of their respective owners.
Page 52 of 52